Immunologic systemImmunologic system

Tianjin general hospital Tianjin general hospital

JiangLihong JiangLihong

• Characteristics of the immunologic Characteristics of the immunologic systemsystem

• Immunodeficiency diseasesImmunodeficiency diseases

Characteristics of the Characteristics of the immunologic systemimmunologic system

• Definition Definition

• ClassificationClassification

• Nonspecific immunityNonspecific immunity

• Specific immunitySpecific immunity

Immunodeficiency diseasesImmunodeficiency diseases

• ClassificationClassification• Some common diseases due to immunoSome common diseases due to immuno

deficiency in children (congenital hypogdeficiency in children (congenital hypogammaglobulinemia, infant transient hypammaglobulinemia, infant transient hypogammaglobulinemia, selective IgA defiogammaglobulinemia, selective IgA deficiency, congenital thymus dysplasia [Diciency, congenital thymus dysplasia [DiGeorge’s syndrome], AIDS)George’s syndrome], AIDS)

DefinitionDefinition

• Immunity is a protective reaction of Immunity is a protective reaction of the body, which could keep the body the body, which could keep the body in a in a soundsound and and stablestable status. The status. The immunologic system is that part of a immunologic system is that part of a host defense mechanism.host defense mechanism.

• The genesis and development of the huThe genesis and development of the human immune system arises in the early eman immune system arises in the early embryo, but it is still not completely matumbryo, but it is still not completely mature at birth. It develops gradually up to adre at birth. It develops gradually up to adult level with increasing age. Therefore, iult level with increasing age. Therefore, in children, especially infants, there is a n children, especially infants, there is a pphysiologic hypoimmunityhysiologic hypoimmunity state. state.

ClassificationClassification

• Nonspecific immunitNonspecific immunityy

Skin,mucous membranSkin,mucous membrane,e,Phagocytosis (mainly laPhagocytosis (mainly la

rge mononuclear cellrge mononuclear cells, neutrophils)s, neutrophils)

Complement systemComplement system

• Specific immunitySpecific immunity

T-lymphocytesT-lymphocytes

B-lymphocytesB-lymphocytes

ClassificationClassification

• Immune organs Immune organs and tissuesand tissues

Bone marrow, Bone marrow, thymus gland, thymus gland, spleen, lymph spleen, lymph node, lymph tissuenode, lymph tissue

• ImmunocytesImmunocytes Macrophages, B cells,Macrophages, B cells,

T cell,natural killer cT cell,natural killer cellsells

B cellB cell

T cellT cell

macrophagemacrophage

macrophagemacrophage

macrophagemacrophage

macrophagemacrophage

macrophage3.jpg

neutrophilneutrophil

basophilbasophil

EosinophilEosinophil

Weight of thymus glandWeight of thymus gland

• Born:10-15gBorn:10-15g

• 6-13year:30g6-13year:30g

• 20year:20g20year:20g

• Old man:less than 10gOld man:less than 10g

Thymus glandThymus gland

Weight of spleenWeight of spleen

• Born:5-10gBorn:5-10g

• 20year:100-300g20year:100-300g

• Old man:slight smallOld man:slight small

appenditis

Nonspecific defense Nonspecific defense mechanismsmechanisms

• Nonspecific defense mechanisms are priNonspecific defense mechanisms are primitive in phylogenetic sense but remain mitive in phylogenetic sense but remain highly effective in protecting humans frohighly effective in protecting humans from the environment .m the environment .

• The nonspecific defense system can be tThe nonspecific defense system can be thought of as consisting of three componhought of as consisting of three components:physical,cellular,and humoral.ents:physical,cellular,and humoral.

Nonspecific defense Nonspecific defense mechanismsmechanisms• The first line of host defense is the The first line of host defense is the

mechanical barrier represented by the mechanical barrier represented by the skin and mucous membranes lining the skin and mucous membranes lining the respiratory and gastrointestinal tracts.respiratory and gastrointestinal tracts.

• Nonspecific factors such as the Nonspecific factors such as the unsaturated fatty acids in the skin, unsaturated fatty acids in the skin, gastric secretions in the stomach, and gastric secretions in the stomach, and cilia lining the respiratory tree may cilia lining the respiratory tree may contribute to the overall barrier effect.contribute to the overall barrier effect.

Nonspecific defense Nonspecific defense mechanismsmechanisms

• If the mechanical barriers are penetrateIf the mechanical barriers are penetrated, both nonspecific cellular and humoral d, both nonspecific cellular and humoral factors contribute to protection of the hfactors contribute to protection of the host.ost.

• particular importance are the phagocytiparticular importance are the phagocytic cells and humoral factors such as comc cells and humoral factors such as complement, interferon,and lymphokines.plement, interferon,and lymphokines.

Phagocyte

Adaptive immune

response

Lymphocytes

Innate immune

response

Biochemical barriers

Skin

Pathogens

Physical Cellular Humoral

SkinMucous membranesMucociliary system

Phagocytic cellsNeutrophilsMacrophagesMonocytesEosinophilsReticuloendothelial system

LysosomesInterferonComplementLactoferrinlymphokines

•Nonspecific host defense mechanisms

Character of nonspecific Character of nonspecific immunity in childrenimmunity in children

• Nonspecific immunity plays a role in the Nonspecific immunity plays a role in the immune system by presenting a physical immune system by presenting a physical barrier such as phagocytosis and the cobarrier such as phagocytosis and the complement system which consists of mormplement system which consists of more 20 serum proteins.e 20 serum proteins.

Components and characters Components and characters of nonspecific immunityof nonspecific immunity

ComponentsComponents FunctionFunction Characters in Characters in childrenchildren

Skin and mucosaSkin and mucosa Physical barrierPhysical barrier Thin,damaged Thin,damaged easilyeasily

Lymph nodesLymph nodes FiltrationFiltration Imperfect,infection Imperfect,infection diffuse easilydiffuse easily

Macrophage Macrophage phagocytosisphagocytosis Perfect after 34w Perfect after 34w GAGA

Blood-brain barrier Blood-brain barrier placental barrierplacental barrier

barrierbarrier Penetration,meningPenetration,meningitis,intrauterine itis,intrauterine infectioninfection

Tissue fluid:gastric Tissue fluid:gastric juice,lactic acid juice,lactic acid from skinfrom skin

Kill bacteria Kill bacteria Low gastric Low gastric acidity,fail to acidity,fail to destroy destroy bacteria,low lactic bacteria,low lactic acid from skinacid from skin

Complement propeComplement properdinrdin

Kill bacteriaKill bacteria 35-70%of that of 35-70%of that of adultadult

60%of content for 60%of content for adultadult

Specific immunitySpecific immunity

• The human immune system arises in the embryo fThe human immune system arises in the embryo from gut-associated tissue. Pluripotential hematorom gut-associated tissue. Pluripotential hematopoietic stem cells first appear in the yolk sac at 2.poietic stem cells first appear in the yolk sac at 2.5-3weeks of GA and migrate to the fetal liver at th5-3weeks of GA and migrate to the fetal liver at the fifth week of gestation;later they reside in the boe fifth week of gestation;later they reside in the bone marrow, where they remain throughout life.ne marrow, where they remain throughout life.

• Lymphoid stem cells develop from such precursor Lymphoid stem cells develop from such precursor cells and differentiate into T and B cells. T and B-lcells and differentiate into T and B cells. T and B-lymphocytes are the only components of the immymphocytes are the only components of the immune system that have antigen-specific recognition une system that have antigen-specific recognition capabilities.capabilities.

Specific immune Specific immune mechanismsmechanisms

• It is now evident that the lymphocyte is tIt is now evident that the lymphocyte is the cell line responsible for most immune he cell line responsible for most immune reactions.reactions.

• Two main types of immunity are now recTwo main types of immunity are now recognized:ognized:cell-mediated immunity and hcell-mediated immunity and humoral immunityumoral immunity

Specific Cellular ImmunitySpecific Cellular Immunity

• The T cell is an effector cell of cyto-immThe T cell is an effector cell of cyto-immunity.unity.

• The major T cell subgroups currently are The major T cell subgroups currently are defined helper, suppressor and killer podefined helper, suppressor and killer populations.pulations.

T cellT cell

T-cell functionsT-cell functions

• Microbial resistance particularly for Microbial resistance particularly for intracellular parasites, virus and intracellular parasites, virus and fungi.fungi.

• Transplantation immunity.Transplantation immunity.

• Tumor rejectionTumor rejection..

• Skin delayed hypersensitivity.Skin delayed hypersensitivity.

Characteristics of T-cell in Characteristics of T-cell in childrenchildren

• During the fetal period the T cell During the fetal period the T cell system is undeveloped, fetal system is undeveloped, fetal intrauterine infection is not rare.intrauterine infection is not rare.

• During the neonatal period the T cell During the neonatal period the T cell system is well developed.system is well developed.

Specific Humoral ImmunitySpecific Humoral Immunity

• B-cell development begins in the fetal livB-cell development begins in the fetal liver before 7 weeks of gestation.er before 7 weeks of gestation.

• B-cell have an important function in micB-cell have an important function in microbial resistance ,especially to bacteria.robial resistance ,especially to bacteria.

• B-cell products, immunoglobulins, can bB-cell products, immunoglobulins, can be divided into 5 major classes.e divided into 5 major classes.

B cellB cell

The 5 major classes of immunoThe 5 major classes of immunoglobulins globulins • IgGIgG• IgMIgM• IgAIgA• IgDIgD• IgEIgE

IgGIgG• It is the It is the most abundantmost abundant Ig of the body. Ig of the body.• The only Ig The only Ig can cross the placentacan cross the placenta..• The level in a premature infant is low, because IgThe level in a premature infant is low, because Ig

G gets through the placenta from mother mainly G gets through the placenta from mother mainly after after 32 weeks32 weeks of gestation. of gestation.

• Maternal IgG plays an important role in infection Maternal IgG plays an important role in infection resistance within the 6 months of life.resistance within the 6 months of life.

• There is There is physiological hypogammaglobulinemphysiological hypogammaglobulinemiaia period. period.

• It has a half-life of 21 days and is the principal tyIt has a half-life of 21 days and is the principal type of antibody appearing in a secondary immunpe of antibody appearing in a secondary immune response.e response.

IgMIgM

• It is the major antibody resisting Gram nIt is the major antibody resisting Gram negative bacilli infections.egative bacilli infections.

• It can not cross the placenta.If IgM in the It can not cross the placenta.If IgM in the umbilical blood is at the level of more thumbilical blood is at the level of more than 20mg/dl ,it indicates there has been aan 20mg/dl ,it indicates there has been an intrauterine infection.n intrauterine infection.

• It has a half-life of 4 to 5 days.It has a half-life of 4 to 5 days.

IgAIgA

• It is produced by the lymphoid tissues which lIt is produced by the lymphoid tissues which lining the gastrointestinal, respiratory and genining the gastrointestinal, respiratory and genitourinary tracts coming in contact with antigitourinary tracts coming in contact with antigen after birth.en after birth.

• It is an important factor for resisting mucosal It is an important factor for resisting mucosal infections.infections.

• It is in high concentration in the colostrum.It is in high concentration in the colostrum.• IgA exist in 2 forms: monomeric in the serum IgA exist in 2 forms: monomeric in the serum

and dimeric in the secretion. and dimeric in the secretion.

IgDIgD

• The IgD exists in minute quantities in the circulatThe IgD exists in minute quantities in the circulation.ion.

• Along with IgM, it is the immunoglobulin found Along with IgM, it is the immunoglobulin found most frequently on B lymphocytes.most frequently on B lymphocytes.

• Its exact function is not well understood at preseIts exact function is not well understood at present.nt.

• IgD crosses the placenta with difficult.IgD crosses the placenta with difficult.• The amount of IgD is low in the blood of the neoThe amount of IgD is low in the blood of the neo

nate, reaching to 20% of the adult when 5 years.nate, reaching to 20% of the adult when 5 years.

IgEIgE

• The IgE is associated with immediate hypersensitThe IgE is associated with immediate hypersensitivity reaction. It exists in small quantities in the ciivity reaction. It exists in small quantities in the circulation.rculation.

• Through its Fc fragment it binds to tissue mast ceThrough its Fc fragment it binds to tissue mast cells and circulating basophils.lls and circulating basophils.

• When two IgE molecules bound to these receptorWhen two IgE molecules bound to these receptors are bridged by an antigen such as ragweed polls are bridged by an antigen such as ragweed pollen, the cells then can release the mediators charaen, the cells then can release the mediators characteristic of the allergic response, such as histamicteristic of the allergic response, such as histamine and slow reactive substance of anaphylaxis.(nne and slow reactive substance of anaphylaxis.(next)ext)

IgEIgE

• IgE crosses the placenta with difficult.IgE crosses the placenta with difficult.• The amount of IgE is also very low in the The amount of IgE is also very low in the

neonate. It may be obtained from breast neonate. It may be obtained from breast milk, and reach to the level of the adult milk, and reach to the level of the adult by about 7 years age. by about 7 years age. IgE is an antibody IgE is an antibody which bring a type I allergic reactionwhich bring a type I allergic reaction..

Immunodeficiency diseasesImmunodeficiency diseases

• Primary Immunodeficiency Diseases: coPrimary Immunodeficiency Diseases: congenital dysplasias or genetic abnormalingenital dysplasias or genetic abnormalities.They develop symptoms after birth.ties.They develop symptoms after birth.

• Secondary Immunodeficiency diseasesSecondary Immunodeficiency diseases(Acquired Immunodeficiency Diseases): (Acquired Immunodeficiency Diseases): relation to infection by the human immurelation to infection by the human immunodeficiency virus), which was noted in nodeficiency virus), which was noted in 1981.1981.

ClassificationClassification

• Humoral immunity deficiency(50%)Humoral immunity deficiency(50%)• Cellular immunity deficiency(10%)Cellular immunity deficiency(10%)• Combined immunity deficiency(20%)Combined immunity deficiency(20%)• Phagocytic deficiency diseases(18%)Phagocytic deficiency diseases(18%)• Complement system defect(2%)Complement system defect(2%)

Primary immunodeficincy diPrimary immunodeficincy diseasesease

common manifestationcommon manifestation

Recurrent infection and Recurrent infection and chronic infectionchronic infection

• infection site :respiratoryinfection site :respiratory• Pathogen:Pathogen: humoral immunity deficincy : pyogenichumoral immunity deficincy : pyogenic cellular immunitydeficiency: virus,cellular immunitydeficiency: virus, tuberculosis,fungituberculosis,fungi complement system:Neisseriacomplement system:Neisseria• Course of infection: recurrent or chronicCourse of infection: recurrent or chronic

Autoimmunologic disease and Autoimmunologic disease and lymphomalymphoma• Lymphoma,especially B lymphoma(50%)Lymphoma,especially B lymphoma(50%)• Lymphocyte leukemia(12.6%)Lymphocyte leukemia(12.6%)• Lymphoma and Hodgkin’s(8.6%)Lymphoma and Hodgkin’s(8.6%)• Glandular tumor(9.2%)Glandular tumor(9.2%)• Others(19.2%)Others(19.2%)• Hemolytic anemia, thrombocytopenic puHemolytic anemia, thrombocytopenic pu

rpura, systemic lupus erythematous, typrpura, systemic lupus erythematous, type I diabetese I diabetes

Congenital hypogammaglobulCongenital hypogammaglobulinemiainemia• Onset: after 6 months of age when the IgG froOnset: after 6 months of age when the IgG fro

m mother has been exhausted.m mother has been exhausted.• Sex:because it has two hereditary modes, the Sex:because it has two hereditary modes, the

disease might occurs in males or females.disease might occurs in males or females. X-li X-linkednked hypogammaglobulinemia also called Br hypogammaglobulinemia also called Bruton’s disease, which only occurs in boys.uton’s disease, which only occurs in boys.

• Recurrent infection: mainly bacterial infection.Recurrent infection: mainly bacterial infection.• Autoimmune disease such as rheumatoid arthAutoimmune disease such as rheumatoid arth

ritis.ritis.• Malignant tumor: leukemia.Malignant tumor: leukemia.

Congenital hypogammaglobulCongenital hypogammaglobulinemiainemia• Small or absent tonsil, lymph node, but Small or absent tonsil, lymph node, but

normal thymusnormal thymus• Lab finding: the tests of humoral-immunLab finding: the tests of humoral-immun

ity are of low functional status, the tests ity are of low functional status, the tests for cellular-immunity are normal.for cellular-immunity are normal.

• Treatment: IVIG 400mg/kg /3-4week untiTreatment: IVIG 400mg/kg /3-4week until IgG concentration is 1000mg/dll IgG concentration is 1000mg/dl

Infant transient hypogammaglInfant transient hypogammaglobulinemiaobulinemia• Production of immune globulin is delayed to Production of immune globulin is delayed to

9-21 months after birth.9-21 months after birth.• Clinical features are similar to congenital hypoClinical features are similar to congenital hypo

gammaglobulinemia.gammaglobulinemia.• Self-limited: the level of Ig increasing with incrSelf-limited: the level of Ig increasing with incr

easing age.easing age.• It does not relapse after revival.It does not relapse after revival.• Bone marrow smear or lymphonodus biopsy cBone marrow smear or lymphonodus biopsy c

ould show plasmacyte. (the key point different ould show plasmacyte. (the key point different from congenital hypogammaglobulinemia)from congenital hypogammaglobulinemia)

Selective IgA deficiencySelective IgA deficiency

• It has a high incidence in PID, about is 1/It has a high incidence in PID, about is 1/500-1/700.500-1/700.

• Slight symptoms of recurrent respiratorSlight symptoms of recurrent respiratory infections and chronic diarrhea, the pay infections and chronic diarrhea, the patient may be alive to adult even old.tient may be alive to adult even old.

• Associated with autoimmune disorders, Associated with autoimmune disorders, especially systemic lupus erythematous especially systemic lupus erythematous and rheumatoid arthritis. (next)and rheumatoid arthritis. (next)

Selective IgA deficiencySelective IgA deficiency

• Occasionally occur malignant tumor.Occasionally occur malignant tumor.• Serum IgA is low, other Igs are normal.Serum IgA is low, other Igs are normal.• Avoid utilizing IgA containing agent in trAvoid utilizing IgA containing agent in tr

eatment. Now ,there is no satisfactory theatment. Now ,there is no satisfactory therapy for this disease.erapy for this disease.

Congenital thymus dysplasiaCongenital thymus dysplasia

• In 1965, DiGeorge first discovered this diIn 1965, DiGeorge first discovered this disease, so called DiGeorge syndrome, inclsease, so called DiGeorge syndrome, including thymus dysplasia, hypocalcemia, uding thymus dysplasia, hypocalcemia, congenital heart disease and facial deforcongenital heart disease and facial deformities.mities.

Congenital thymus dysplasiaCongenital thymus dysplasia

• Hypocalcemia during the neonatal period Hypocalcemia during the neonatal period frequently is the initial presentation.frequently is the initial presentation.

• Special facial features: fish-like mouth , sSpecial facial features: fish-like mouth , short philtrum, small mandible, defective hort philtrum, small mandible, defective ears.ears.

• Congenital defect of the aorta and heart.Congenital defect of the aorta and heart.• Recurrent severe infection s of fungi or virRecurrent severe infection s of fungi or vir

us appear soon after birth.(next)us appear soon after birth.(next)

Congenital thymus dysplasiaCongenital thymus dysplasia

• No thymic shadow is shown in a chest X-rNo thymic shadow is shown in a chest X-ray film.ay film.

• Lb exam reveals a poor cellular-immune fLb exam reveals a poor cellular-immune function and a normal humoral-immune function and a normal humoral-immune function.unction.

• Avoid attenuated alive vaccines and blooAvoid attenuated alive vaccines and blood transfusion.d transfusion.

• Treatment: thymus transplantation.Treatment: thymus transplantation.

Treatment of PIDTreatment of PID

General treatment: take care of patient General treatment: take care of patient specially precaution and treat infectionspecially precaution and treat infection

Substitutive therapy: IVIG; plasma:20mg/dlSubstitutive therapy: IVIG; plasma:20mg/dl

Immune rebuild:Immune rebuild:

1)Thymus tissue transplantation: not good1)Thymus tissue transplantation: not good

2)Stem cell transplantation2)Stem cell transplantation

Gene treatmentGene treatment

HIV infectionHIV infection

HIV(human HIV(human immunodeficiency virus)immunodeficiency virus)

• First reported in 1981,USAFirst reported in 1981,USA• Can damage helper T cell,lead to opportCan damage helper T cell,lead to opport

unist infection and tumorunist infection and tumor• Has ten genes: gag, pol, env, vif, vpr, tat, Has ten genes: gag, pol, env, vif, vpr, tat,

rev, vpu, nef, vpxrev, vpu, nef, vpx

Transmission route to Transmission route to childrenchildren

• IntrapartumIntrapartum• IntrauterineIntrauterine• Breast-feeding(25-40%)Breast-feeding(25-40%)• Infected blood products and contaminatInfected blood products and contaminat

ed needlesed needles

Reduction of vertical Reduction of vertical transmission of HIVtransmission of HIV

• Avoidance of breast-feedingAvoidance of breast-feeding• Use of antenatal, perinatal and postnataUse of antenatal, perinatal and postnata

l antiretroviral drugs to reduce viral loadl antiretroviral drugs to reduce viral load• Avoidance of labor and contact with the Avoidance of labor and contact with the

birth canal by selective cesarean section birth canal by selective cesarean section deliverydelivery

HIV-infected childrenHIV-infected children

• Infected children may remain asymptomatic fInfected children may remain asymptomatic for months or years before progressing to severor months or years before progressing to severe disease and immunodeficiency.e disease and immunodeficiency.

• Clinical presentation varies with the degree of Clinical presentation varies with the degree of immunosuppression.immunosuppression.

Mild: lymphadenopathyMild: lymphadenopathyModerate: recurrent bacterial infections, candidiModerate: recurrent bacterial infections, candidi

asis, chronic diarrheaasis, chronic diarrheaSevere: opportunist infections, severe failure to tSevere: opportunist infections, severe failure to t

hrive, encephalopathyhrive, encephalopathy

diagnosisdiagnosis

• PCR find HIV DNAPCR find HIV DNA

Treatment-antivirusTreatment-antivirus

• NRTI: nucleoside reverse transcriptaseNRTI: nucleoside reverse transcriptase• NNRTI:non nucleoside reverse transcriptNNRTI:non nucleoside reverse transcript

asease• Proteinase inhibitorProteinase inhibitor

PROTEINASE INHIBITORPROTEINASE INHIBITOR

• Indinavir(IDV):500mg/m q8hIndinavir(IDV):500mg/m q8h

• Nelfinavir(NVP):20-30mg/kg q8hNelfinavir(NVP):20-30mg/kg q8h

• Ritonavir(RTV):350-400mg/m q12hRitonavir(RTV):350-400mg/m q12h

NRIT(nucleoside reverse NRIT(nucleoside reverse transcriptase inhibitor)transcriptase inhibitor)

• Zidovudine(ATZ):160mg/m q8hZidovudine(ATZ):160mg/m q8h

• Dideoxyinosine(DDL):90mg/m q12hDideoxyinosine(DDL):90mg/m q12h

• Lamivuding(3TC):4mg/kg q12hLamivuding(3TC):4mg/kg q12h

NNRIT(nonnucleoside reverse NNRIT(nonnucleoside reverse transcriptase)transcriptase)• Efavirenz:10kg-- 200mg qdEfavirenz:10kg-- 200mg qd 15kg-- 250mg qd15kg-- 250mg qd 20kg-- 350mg qd20kg-- 350mg qd 32.5kg-- 400mg qd32.5kg-- 400mg qd 40kg-- 600mg qd(max)40kg-- 600mg qd(max)

QuestionsQuestions• Definition: immunologic systemDefinition: immunologic system• Specific immunity includes: cellular immunitSpecific immunity includes: cellular immunit

y and humoral immunityy and humoral immunity• The 5 major classes of immunoglobulins are The 5 major classes of immunoglobulins are

denoted: IgG, IgM, IgA, IgD, IgA.denoted: IgG, IgM, IgA, IgD, IgA.• Which is the most abundant Ig of the bodyWhich is the most abundant Ig of the body• Which Ig can cross the placenta?Which Ig can cross the placenta?• Classification of PIDClassification of PID

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